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In The Journal of pharmacology and experimental therapeutics

In the wake of the COVID-19 pandemic, drug repurposing has been highlighted for rapid introduction of therapeutics. Proposed drugs with activity against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential targets for the organic cation (OC) secretory transporters of kidney and liver, i.e., the basolateral Organic Cation Transporters, OCT1 and OCT2; and the apical Multidrug And Toxin Extruders, MATE1 and MATE2-K. We selected several compounds proposed to have in vitro activity against SARS-CoV-2 (chloroquine, hydroxychloroquine, quinacrine, tilorone, pyronaridine, cetylpyridinium and miramistin), to test their interaction with OCT and MATE transporters. We used Bayesian Machine learning models to generate predictions for each molecule with each transporter and also experimentally determined IC50 values for each compound against labelled substrate transport into CHO cells that stably expressed OCT2, MATE1 or MATE2-K using three structurally distinct substrates (atenolol, metformin and 1-methyl-4-phenylpyridinium (MPP)) to assess the impact of substrate structure on inhibitory efficacy. For the OCTs substrate identity influenced IC50 values, though the effect was larger and more systematic for OCT2. In contrast, inhibition of MATE1-mediated transport was largely insensitive to substrate identity. Unlike MATE1, inhibition of MATE2-K was influenced, albeit modestly, by substrate identity. Cu,max/IC50 ratios were used to identify potential clinical DDI recommendations; all the compounds interacted with the OCT/MATE secretory pathway, most with sufficient avidity to represent potential DDI issues for secretion of cationic drugs. This should be considered when proposing cationic agents as repurposed antivirals. Significance Statement Drugs proposed as potential COVID-19 therapeutics based on in vitro activity data against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential interactors with the OCT/MATE renal secretory pathway. We tested seven such molecules as inhibitors of OCT1/2 and MATE1/2-K. All the compounds blocked transport activity regardless of substrate used to monitor activity. Suggesting that plasma concentrations achieved by normal clinical application of the test agents could be expected to influence the pharmacokinetics of selected cationic drugs.

Martinez Guerrero Lucy Jazmin, Zhang Xiaohong, Zorn Kimberley M, Ekins Sean, Wright Stephen H

2021-Jul-12

Organic cation uptake / efflux (OCTs, ENTs), drug-drug interactions, renal transport